Histamine receptor pharmacology has revealed three subtypes of receptors which mediate (or are associated with) the activity of histamine. These receptors are most commonly referred to as H.sub.1, H.sub.2, and H.sub.3. The most recently discovered of these receptors is the H.sub.3 -histamine receptor. Early studies suggested the presence of another histamine receptor when it was demonstrated that histamine inhibits its own synthesis and release in brain slices by a negative feedback process operating at the level of histaminergic nerve-endings (see, for example,. Arrang, J. M. et al. Nature 302:832-837 (1983)). More recently, the H.sub.3 -receptor has been shown to function as a pre-synaptic autoreceptor inhibiting histamine synthesis and histamine release from neurons, especially in the control nervous system (Arrang, et al. Nature 327:117-123 (1987)). The presence of H.sub.3 -receptors in peripheral tissues has also been reported and here too they appear to be involved with the nervous system. Thus, histamine depresses sympathetic neurotransmission in the guinea pig mesenteric artery by interacting with H.sub.3 -receptors on the perivascular nerve terminals (Ishikawa and Sperelakis, Nature 327:158 (1987)). This important observation suggests that histamine may control the release of other neurotransmitters (Tamura et al., Neuroscience 25:171 (1988)). Inhibitory histamine H.sub.3 -receptors also exist in the guinea pig ileum where their role appears to be to modify the magnitude of histamine contraction, rather than affecting histamine release (Trzeciakowski, J. Pharmacol. Exp. Therapy 243:847 (1987)). Particularly intriguing is the discovery of H.sub.3 -receptors in the lung (Arrang et al. Nature 327: 117-123 (1987)). The presence of histamine H.sub.3 -receptors in the lung raises the question of whether they control histamine release in anaphylaxis and whether they may be manipulated to provide therapy in asthma. Indeed it has been suggested that H.sub.3 -receptors may have a modulating role on excitatory neurotransmission in airways. Generally, however, H.sub.3 -receptor inhibition tends to increase histamine activity, with potentially detrimental effects. Thus, it is desirable to avoid introducing H.sub.3 -receptor antagonists that act on peripheral tissues.
Histamine H.sub.3 -receptor activation was found to inhibit acetylcholine release in a guinea pig ileum model (Poli et al., Agents and Actions 33: 167-169). Selective H.sub.3 -receptor blockers reversed the histamine-induced inhibitory effect. Histamine also decreased serotonin release; this effect was reversed with an H.sub.3 -antagonist, and was suggested to operate via the histamine H.sub.3 -receptors (Schlicker et al., Naunyn-Schmiedaberg's Arch. Pharmacal. 337:588-590 (1988). Activation of H.sub.3 -receptors was found to inhibit excitatory presynaptic potentials (Arrang et al., (J. Neurochem. 51:105 (1988)).
One reported highly specific competitive antagonist of histamine H.sub.3 -receptors is thioperamide (Arrang et al., Nature 327:117-123 (1987)). Although thioperamide is a very potent antagonist in vitro (K.sub.i =4.3 nmol/L), relatively high doses are required in vivo to inhibit histamine release from the brain in rats (Ganellin et al., Collect. Czech. Chem. Commun. 56:2448-2455 (1991)). Ganellin et al. suggests that this most probably results from poor penetration through the blood-brain-barrier by this peramide, although the pharmacokinetic properties of thioperamide may also play a role. Moreover, the thiourea functionality found in thioperamide may result in higher intrinsic toxicity of thioperamide.
The previously described literature synthesis of 4-(4-pyridyl)-1H-imidazole is a lengthy procedure requires the conversion of 4-acetylpyridine into its oxime, followed by conversion to the O-tosylate, followed by rearrangement to an .alpha.-aminoketone using elemental potassium in ethanolic hydrogen chloride (G. R. Clemo, et al., J. Chem. Soc. (London 753 (1938)). The latter step is unattractive and potentially hazardous due to the flammability of potassium. The .alpha.-aminoketone is converted to the 2-mercaptoimidazole by treatment with potassium thiocyanate, and subsequent conversion (P. Neber et al., Liebigs Ann. Chem., 449:109 (1926), 467:52 (1928), 493:281 (1932)) to 4-(4-pyridyl)-imidazole is effected using concentrated nitric acid. This process leads to a very low yield of 4-(pyridyl)-imidazole.
4-Substituted piperdylimidazoles have been prepared by catalytic hydrogenation of the corresponding 4-pyridyl-imidazole. The 4-pyridyl-imidazole is obtained by reduction of the 2-mercaptoimidazole. (P. Neber, et al. Liebig Ann. Chem., 449:109 (1926), 467:52 (1928), 493:281 (1932). Schunack, W., Archiv. Pharma. 306:934 (1973)). Utility of this intermediate in the synthesis of known H.sub.3 -receptor antagonists, including thioperamide (Arrang, et al., Nature, 327:117 (1987)) has been described by Arrang in U.S. Pat No. 4,707,487 issued on Nov. 17, 1987 which discloses (4-imidazolyl)piperidine derivatives that are useful to control the release of cerebral histamine and to increase the rate of renewal of cerebral histamine.
It is an object of the present invention to provide a novel process for the preparation of intermediates useful in the synthesis of novel histamine receptor antagonists, in particular histamine H.sub.3 -receptor antagonists.
It is a further object of the present invention to provide a novel process for the preparation of intermediates of known histamine receptor antagonists.
In addition, it is an object of the present invention to provide a process for the preparation of histamine receptor antagonists or their intermediates in high yield while using fewer steps than the prior art.
It is yet another object of the present invention to provide a novel process for the preparation of potent histamine receptor antagonists, in particular histamine H.sub.3 -receptor antagonists that are better able to penetrate the blood-brain-barrier than previously reported compounds and that have reduced toxicity compared to other known histamine antagonists.